From genes to therapies: the role of animal models Alcino J. Silva * , Ype Elgersma, Rui M. Costa Departments of Neurobiology, Psychiatry, and Psychology, and Brain Research Institute, University of California, Los Angeles, 695 Young Drive South, Room 2554, Box 951761, Los Angeles, CA 90095-1761, USA Accepted 16 January 2001 Abstract Recent excitement with the human genome project stems partly from the belief that the identi®cation of the genes underlying the nearly 12 000 known genetic disorders will bring us closer to the development of therapies. However, it is still unclear how genetic information can be translated into treatments for inherited disorders. Here, we will review how molecular, physiological and behavioral studies in a mouse model of neuro®bromatosis type I (NF1) have improved our understanding of the learning de®cits associated with this tragically common genetic disorder. We also discuss insights from these studies about the nature and usefulness of animal models of brain disorders. Similar issues are also likely to impact the study of other neurological and psychiatric disorders. q 2001 Association for Research in Nervous and Mental Disease. Published by Elsevier Science B.V. All rights reserved. Keywords: Animal model; Heritable disease; Gene therapy; Neuro®bromatosis; Learning; Memory 1. Introduction The goal of the human genome project is the mapping and sequencing of the entire genome. It is with great anticipation that the scienti®c community awaited the completion of the human genome project, since this information will revolu- tionize modern medicine in ways that we are only starting to realize. Of immediate consequence is the enormous impact that the complete sequence of the human genome will have on the lengthy and extremely laborious process of mapping and cloning disease loci. There is no doubt that the avail- ability of the sequence will shorten and simplify this process, and that in the next 10 years many of the approxi- mately 12 000 genetic diseases known will be mapped and perhaps cloned. The identi®cation of the genes responsible for inherited disorders is a key ®rst step towards understanding the biolo- gical processes affected by the disorder, and the develop- ment of treatments. With these genes at hand it is possible to generate animal models, and then these models can be used to tackle the disorder. Even though there are numerous encouraging prospects, and a few successes, many of the studies of animal models of brain genetic disorders are in their infancy, and they have yet to yield useful therapies. Here, we will review how molecular, physiological and behavioral studies of animal models of neuro®bromatosis type I (NF1) are starting to elucidate the molecular and cellular etiology of the cognitive de®cits associated with this disorder. Importantly, these studies may also contribute both to a larger understanding of mechanisms of learning, and to insights about the rarely traveled road from genes to therapies. 2. Neuro®bromatosis type I NF1 is a common inherited neurological disorder, affect- ing approximately one in 4000 individuals worldwide [1,2]. The gene encodes a 250 kDa protein called neuro®bromin, which includes a GAP (GTPase-activating) domain that accelerates the inactivation of p21 ras by stimulating its GTPase activity [3±5]. p21 ras plays a pivotal role in several signal pathways including those involving the MAP kinase cascade, and PI3-Kinase. However, neuro®bromin can also regulate Ras signaling by mechanisms independent of its GAP function because it is effective in decreasing the activ- ity of p21 ras mutant proteins resistant to GTPase stimulation [6]. In addition, studies in the larval neuromuscular junction of Drosophila melanogaster suggested that neuro®bromin modulates the rutabaga-encoded adenylyl cyclase [7,8], indicating that neuro®bromin may be involved in the regu- lation of multiple signaling pathways. Importantly, a muta- tion in the NF1 gene that speci®cally abolishes the Ras- GTPase-activating function of neuro®bromin without Clinical Neuroscience Research 1 (2001) 187±193 1566-2772/01/$ - see front matter q 2001 Association for Research in Nervous and Mental Disease. Published by Elsevier Science B.V. All rights reserved. PII: S1566-2772(01)00005-6 www.elsevier.nl/locate/clires * Corresponding author. Tel.: 11-310-794-6345; fax: 11-310-794-7088. E-mail address: silvaa@mednet.ucla.edu (A.J. Silva).